Degeneration and/or death of cells in the nervous system are major factors in many diseases and medical conditions. Such diseases and conditions include traumatic brain and spinal cord injuries, stroke, neural perfusion secondary to cardiac arterial bypass graft surgery (CABG), Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and other neurodegenerative diseases. It is of interest to prevent or decrease such cell death and degeneration.
Certain compounds are useful as neuroprotective agents. One such compound is insulin-like growth factor 1 (IGF-1) (Scheepens et al, WO00/13650). IGF-1 is a naturally occurring peptide that can decrease the binding of glutamate to the glutamate receptors of neurons (Bourguignon, U.S. Pat. No. 5,804,550). IGF-1 can also decrease neuronal degradation caused by damage and disease. IGF-1 is cleaved by proteolysis in viva to give des1-3 IGF-1 and the N-terminal tripeptide Gly-Pro-Glu (GPE). GPE and analogues have been found to be neuroprotective (Gluckman et al, U.S. Pat. No. 6,187,906 incorporated herein by reference).
However, such peptides are far from ideal for the treatment of neural death and degeneration especially as they are rapidly metabolised in vivo. There is a need for compounds that provide neuroprotective and neuroregenerative properties and are more metabolically stable especially as regards resistance to proteases.
A derivative of GPE; cyclic Pro-Gly (“cPG”), a diketopiperazine, has been shown to be neuroprotective and neuroregenerative. cPG was found to prevent toxic neural degeneration and cell death and to promote neurite outgrowth in neurons (Guan et al, PCT/US02/36235 incorporated herein by reference). Diketopiperazine analogues of thyrotropin-releasing hormone (TRH) are known to be neuroprotective (Kozikowski et al WO99/40931).
Peripheral neuropathy is a dysfunction of peripheral nerves the symptoms of which may include varying degrees of sensory disturbances, pain or muscular atrophy, diminished reflexes or vasomotor symptoms (The Merck Manual of Diagnosis and Therapy, 18th ed. 2006). Depending on the distribution of a peripheral neuropathy it can be classified as either a mononeuropathy, most commonly caused by trauma and confined to a single limb or nerve, or a polyneuropathy, a diffuse peripheral nerve disorder. Polyneuropathies can arise from toxic causes (eg, pyridoxine intoxication, chemotherapy), metabolic conditions (eg, AIDS, diabetes mellitus, or cancer) or autoimmune response. Peripheral neuropathy may affect motor, sensory or both types of neural fibres. Sensory peripheral neuropathies are characterized by degeneration of sensory neurons, particularly the large axons of the proximal and distal nerves (large sensory fibre axonopathy). In the cases of lower extremity diabetic neuropathy and vitamin B6-induced peripheral neuropathy, the distal peroneal and sural sensory nerves that descend from the sciatic nerve can be affected. Conduction velocities of the sensory nerves can be decreased, and loss of sensation can lead to functional incapacity, such as gait ataxia (abnormal locomotion).
At present there is a paucity of treatments available for neuropathic conditions, and these are limited to drugs for symptomatic relief of neuropathic pain. The common treatment options include antidepressants, such as duloxetine (which provide some neuropathic pain relief independent of effects on depression) and anticonvulsants, such as gabapentin. These only have appreciable efficacy in a subset of patients, and no disease-modifying or disease-halting drugs are currently available. A disease-modifying treatment for neuropathy in a chronic condition such as diabetes would need to be given throughout the course of the disease to prevent its progression. Given the chronic nature of such treatment, any potential drug should be suitable for oral delivery.